Disorders of eye movement, particularly smooth pursuit eye movement (SPEM), remain one of the few specific findings in schizophrenia. Despite many studies which find abnormal SPEM in schizophrenia, their precise nature and relationship to the etiology and treatment of schizophrenia remain unclear. This project attempts to better define the pathophysiology of eye movement disorders by studying patients with schizophrenia, other psychiatric disorders and normal controls utilizing a computerized infrared oculographic recording system which allows precise measurement of eye velocity. We have observed differences in SPEM gain and types of saccades in SPEM between schizophrenic patients and controls. We observed intrusive saccades but not corrective saccades to distinguish patients from normals. We observed no effect of typical neuroleptics on these variables, confirming previous findings. However, we find that the atypical neuroleptic, clozapine, significantly reduces SPEM gain and increases catch-up saccades, while intrusive saccades remain stable, regardless of medication or drug-free state. Also, saccades correlate with response to treatment with clozapine. We observed in schizophrenic patients only that SPEM gain is correlated with performance on the Wisconsin Card Sort, a test of frontal lobe function. To further investigate the pathophysiology underlying eye movement dysfunction in schizophrenia. We are analyzing performance on frontal lobe eye movement tasks, as well as changes in regional cerebral blood flow during eye movement tasks utilizing positron emission tomography (PET). Finally, we have examined genetic aspects of SPEM in discordant monozygotic twins with schizophrenia and have found significant differences in SPEM variables between affected and unaffected co-twins.